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Title: Tissue engineering approaches to the treatment of bisphosphonate-related osteonecrosis of the jaw
Author: Bullock, George
ISNI:       0000 0004 7966 9769
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a disease defined by necrotic jaw bone that has become exposed through the surrounding soft tissue, which affects patients with osteoporosis and bone metastases taking the anti-resorptive bisphosphonate (BP) drugs. Currently this disease is without a specific treatment, in part due to its complex, and not fully understood, pathophysiology. This research used tissue engineering principles to further investigate the effects of BPs on the soft tissue, both in two and three dimensions, and investigated a potential preventative treatment for the disease in vitro. The BPs investigated were pamidronic acid (PA) and zoledronic acid (ZA), two BPs most commonly associated with BRONJ. We explored the effects of PA and ZA on human oral fibroblasts and keratinocytes at clinically relevant concentrations in 2D. Both PA and ZA caused significant reductions to metabolic activity, and further study indicated an increase in apoptosis in fibroblasts, and apoptosis and necrosis in keratinocytes. PA and ZA led to a significant reduction in proliferation, and ZA reduced the adhesion of keratinocytes. However, BPs did not affect cellular migration. A 3D oral mucosa model was used to investigate PA and ZA. PA prevented the stratification of newly formed epithelia and reduced the thickness of healthy epithelia. ZA showed the same effects, but at higher concentrations was also toxic. We began the development of a 3D wound healing assay which could be used as an in vitro model of BRONJ, and indicated that BPs also inhibit oral mucosa wound healing. Finally, we examined the ability of hydroxyapatite (HA) to bind BPs. The abilities of a variety of spectroscopic methods to detect BP binding were tested. Biological assays were also performed to examine the ability of HA to prevent BP toxicity. We have successfully demonstrated that HA could be used to reduce PA and ZA toxicity in vitro. This indicates a potential mechanism by which BRONJ development could be prevented.
Supervisor: Hearnden, Vanessa ; Miller, Cheryl ; McKechnie, Alasdair Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available